Transmission electron micrograph of HIV-1 virus particles. Credit: NIAID
A new study led by Western researchers is the first to identify a factor that could influence how fast the pocket where human immunodeficiency virus (HIV) hides dormant inside of cells shrinks when treated.
HIV is difficult to cure, partly due to the virus’ ability to create a “latent reservoir”—where it hides dormant inside of cells, safe from detection.
“When this virus is expressed within infected cells, it can trick the immune system into not knowing it’s there,” said Jimmy Dikeakos, Schulich Medicine & Dentistry professor and the study’s senior author.
Nef protein, which is expressed by HIV during infection, shields the virus from immune detection. This protein reduces a molecule on the surface of the cell that acts as a marker to help the immune system recognize it is infected.
The study, published in The Lancet Microbe, found the ability of Nef protein to reduce the marker molecule, called cell surface MHC-I, is linked to the speed at which the latent reservoir shrinks during long-term antiretroviral therapy (ART) treatment.
“For people infected with the virus with highly active Nef—meaning the Nef protein is really good at depleting MHC-I molecules from the cell surface—the rate at which the latent reservoir decayed was much slower than in individuals with less active Nef,” said Dikeakos, professor in the department of microbiology and immunology.
The study was part of a large, collaborative global initiative involving the Dikeakos lab in partnership with professor Jessica Prodger at Western, Andrew Redd at the NIH and Rakai Health Sciences Program in Uganda. This discovery opens the door to new strategies that specifically target the Nef protein as a way to help improve treatments for HIV.
Discovery expands treatment possibilities
“By identifying the correlation, it showed that not only can we use treatments that block Nef to target HIV during active replication, but it can be a useful tool to supplement current treatments and cure efforts,” said Mitchell Mumby, postdoctoral researcher at Schulich Medicine & Dentistry and lead author.
Currently, ART treatment is unable to completely eliminate the virus from the body and patients have to take those drugs every day for their entire lives.
“If we’re going to propose curative strategies, we need to understand what the virus is doing in individuals under treatment,” said Dikeakos.
Researchers conducted this study with 14 people living with HIV and receiving ARTs in Uganda over a five-year period where changes in the size of the latent reservoir were measured.
Based on the evidence showing highly active Nef slowed the reduction in the size of the latent reservoir, the researchers are now focusing on developing Nef inhibitors which would directly target the virus rather than the host cell.
“The idea would be to include a potential Nef inhibitor that works well with the current ARTs and other cure approaches currently being explored. The hope is that this approach would result in a targeted reduction in the size of latent reservoirs. It’s not a complete elimination, but we hope by doing this over the long term, people’s prognosis will improve,” said Mumby.
“It’s really about removing those toxic effects from HIV that we know exist, and by reducing this reservoir in this manner, we can mitigate a lot of those effects that are happening.”
This study was also conducted in collaboration with Schulich Medicine & Dentistry researchers Greg Dekaban, Art Poon, Corby Fink, Cassandra Edgar, Steven Trothen and Roux-Cil Ferreira.
More information:
Mitchell J Mumby et al, Association between HIV-1 Nef-mediated MHC-I downregulation and the maintenance of the replication-competent latent viral reservoir in individuals with virally suppressed HIV-1 in Uganda: an exploratory cohort study, The Lancet Microbe (2025). DOI: 10.1016/j.lanmic.2024.101018
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HIV’s latent reservoir: New insights into Nef protein offer potential strategy to improve treatment (2025, March 13)
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